DESCRIPTION: Leishmania chagasi causes the potentially fatal disease visceral leishmaniasis in South America. Cure or protection from all Leishmania sp. infections in mice is caused by a type 1 response with expansion of Th1 CD4+ cells producing interferon-gamma (IFN-g). Our studies of genetically susceptible mice suggest a type 1 response to L. chagasi infection is antagonized by the type 3 cytokine, transforming growth factor-beta (TGF-B). During the adaptive immune response, TGF-B is derived in part from CD4+ T cells, which fall into the recently described "Th3" CD4+ cell subset. During this proposal we will further delineate characteristics of the type 3 response in the context of this infectious disease. We will address the following three hypotheses: First: The antagonistic relationship between TGF-B- and IL-12-producing cells either prevents or promotes the development of protective adaptive immune responses to L. chagasi. The goal of Aim #1 is to examine this hypothesis during chronic infection of mice with L. chagasi, focusing on cytokines (including TGF-B) that are released by immune T cells. We will determine whether analogous immune circuits are expressed in humans during active visceral leishmaniasis. Second: L. chagasi has an inherent propensity to stimulate TGF-B production during the innate immune response. Aim #2 will address whether L. chagasi promotes TGF-B expression or latent TGF-B activation during its initial encounter with host cells. Third: An immunization strategy that suppresses the local production of TGF-B and enhances IL-12 in the vicinity of an immunizing Leishmania antigen(s) will promote a protective immune response. Aim #3 tests this hypothesis using L. chagasi antigens cloned first into a DNA vaccine vector and secondly into Listeriamonocytogenes, an intracellular organism that stimulates IL-12 and a type I response. These studies are intended to delineate the roles of type 1 and type 3 cytokine responses during infection and immunization of murine and human hosts with L. chagasi.